ABSTRACT 22q11 Deletion Syndrome (22q11DS) patients have feeding and swallowing difficulties that compromise their nutritional status and increase nasal, ear, and respiratory infections due to aspiration and reflux. Unfortunately, there are few, if any, therapies to alleviate these significant health problems, and there is no focused basic research into defining the underlying pathology that will inform new therapeutic approaches. We will test the hypothesis that disrupted brainstem motor circuits are a primary site for dysphagia pathology and a primary target for therapeutic intervention. We will advance understanding of the pathology of feeding and swallowing dysfunction in dysphagia using the LgDel animal model for 22q11DS. These studies will provide the foundation for identifying feasible therapeutic approaches and novel drug targets that could improve feeding and swallowing in 22q11DS patients and other children with dysphagia. In Specific Aim 1 we will use a combination of quantitative 3D cellular imaging and cell-class specific analyses of transcriptional changes to assess how diminished 22q11 gene dosage disrupts motor neuron differentiation and innervation in brainstem cranial motor nuclei that regulate feeding and swallowing. In Specific Aim 2 we will use a combination of in vivo behavioral and pathology assays for feeding and swallowing difficulties and quantitative 3D cellular imaging of relevant brainstem CN motor neurons to test if a second mutation in Raldh2, a key synthetic enzyme for production of the developmental signal retinoic acid (RA), corrects feeding, swallowing, and cranial motor neuron differentiation anomalies and dysfunction in LgDel mice. In Specific Aim 3 we will test the hypothesis that altered excitability due to disrupted balance of excitation and inhibition of cranial motor neurons underlies dysphagia due to the 22q11 deletion. We will use a combination of patch-clamp and intracellular recordings to identify changes in the synaptic neurotransmission elicited upon fictive swallowing to brainstem cranial neurons essential for feeding and swallowing and, furthermore, test whether clinically useful drugs in children, such as GABA(A) receptor agonists (benzodiazepines), and/or NMDA receptor antagonists (ketamine) can be repurposed to restore normal activity of swallowing motor neurons. The results of PROJECT 1 will define pediatric dysphagia circuit pathology and provide new pharmacologic, genetic, and genomic insights that will provide a foundation for identifying new targets for novel therapeutic interventions. These results will define key outcomes whose developmental origins will be identified in PROJECT 2 and whose prevention will be the focus of PROJECT 3.